Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Wu, Xueji; Xie, Wei; Xie, Wei; Wei, Wenyi; Guo, Jianping

doi:10.1038/s41419-022-05081-4

Cited by 28 publications

(30 citation statements)

References 243 publications

(304 reference statements)

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“…RSK2, as the downstream signaling mediator of the RAS/ERK pathway, has been shown to play critical roles in oncogenesis and tumor progression in various cancerous diseases, using its NTKD as an output hub to activate its series of oncogenic substrates 41–44 . The involvement of S6K in lymphomagenesis has rarely been reported; however, S6K is also known to be involved in tumorigenesis in various cancers 45 …”

Section: Discussionmentioning

confidence: 99%

“…involvement of S6K in lymphomagenesis has rarely been reported; however, S6K is also known to be involved in tumorigenesis in various cancers. 45 Based on these findings, we examined and successfully demonstrated the antilymphoma efficacy of the RSK/AKT/S6K triple inhibitor TAS0612 by modulating cell cycle regulation and inducing apoptosis in BCL-derived cell lines. Although we did not perform an in vivo mice model study due to the lack of a reliable disease model with our cell lines, we showed the ex vivo efficacy of TA0612 in patient-derived B-lineage lymphoma cells of various disease subtypes, and the clinical activity and safety of TAS0612 are currently under evaluation in a clinical trial involving patients with locally advanced or metastatic solid tumors.…”

Section: F I G U R Ementioning

confidence: 99%

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Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B‐cell lymphomas

Katsuragawa‐Taminishi,

Mizutani,

Kawaji‐Kanayama

et al. 2023

Cancer Science

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B‐cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide‐dependent kinase‐1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL‐derived cell lines examined, including those from activated B‐cell‐like diffuse large B‐cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient‐derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.

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Section: Discussionmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B‐cell lymphomas

Katsuragawa‐Taminishi,

Mizutani,

Kawaji‐Kanayama

et al. 2023

Cancer Science

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“…*p < .05, **p < .01. the phosphorylation of insulin receptor substrate 1 (IRS1) S1101 and desensitization of the insulin receptor. 22,43 S6K1-deficient mice are resistant to HFD-induced hyperglycemia and obesity. 44 We recently reported that gingerenone A, a natural product of the ginger extract, and astaxanthin, a natural, pigmented xanthophyll carotenoid commonly present in microalgae, yeasts, salmon, trout, krill, and other seafood, inhibit S6K1 activity, sensitize the insulin receptor, and increase glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

“…21 Ribosomal protein S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, phosphorylates the insulin receptor substrate (IRS) at S1101 site and subsequently attenuates the activation of the PI3K pathway. 22 S6K1 is constitutively activated under the nutritional overload condition, leading to insulin resistance and inducing obesity. 23 S6K1 is also involved in regulating the expression of a variety of energy expenditure-related genes such as melanocortin-4 receptor (MC4R).…”

Section: Introductionmentioning

confidence: 99%

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

Ji,

Chen,

You

et al. 2023

The FASEB Journal

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Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti‐obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3‐L1 adipocytes by activating TGF‐β‐activated kinase 1 (TAK1), AMP‐activated kinase (AMPK), and Unc‐51 like autophagy‐activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3‐L1 adipocytes, which was blocked by bafilomycin or by beclin‐1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1−/− embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in ob/ob mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K−/− mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide‐mediated anti‐obesity activity.

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“…So, Nrf2 has basic roles for cardiac protection through activating by GCs-beta synthesis which promote mineralocorticoid synthesis for protecting hart layers from K and Na binding toxicity. And, NRF2 drives the cell cycle entry and differentiation, that appears to be beneficial for recovery from blood loss (through activating both Ang2-AT2 and VEGF-A synthesis) [118].…”

Section: Nrf2 Is Necessary For Adopting Anti-inflammatory Growth and ...mentioning

confidence: 99%

GCs-beta and B-arrestins Regulate Nrf2 via NR4As Productive Pathway Mediated by B-adrenergic for Anti-inflammation and Adopting Myocardial and Immune Functions

Tantawi¹

2023

Jap J Clin & Med Res

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The nuclear receptors “NR4As” productive pathway is the so important pathways for activating classic estrogen receptors and are important for regulating the adopted cellular anti-inflammatory growth (mediated by glucocorticoids, Nrf2, Ang2-AT2, and VEGF-A synthesis)which considered as the basic for B-arrestins synthesis which adopt B Adrenergic, and Nrf2 synthesis, that Nrf2 is strong activator to ACE functions for promoting Ang2-AT2 and VEGF-A synthesis for running the adopted anti-inflammatory growth and heme oxygenase. The modulation of oxidative stress will be done by serotonin synthesis (regulated by tryptophan “TGG”) which will promote melatonin synthesis which necessary to activate glucocorticoids productions via NR4A2 pathway followed by B-arrestins and Nrf2 productions for activating Ang2-AT2 and VEGF-A productions. That melatonin synthesis will be associated with GTPase production which promote and activate OPA1 repairs and functions, and responsible for activating glutamine synthesis which stabilize Leu functions through Nrf2 functions. This study concluded that NR4As productive pathway are the important pathway for improving anti-oxidation through improving IL6 productivity to IL17 productions, and is important for glucocorticoids-beta synthesis followed by B-arrestins productions which activate B Adrenergic synthesis that are necessary for activating Nrf2 production that followed by activating ACE for Ang2-AT2 and VEGF-A synthesis for running anti-inflammatory growth, modulating antioxidative stress, activate heme oxygenase, modulating brain function and memories growth , and activating T-cells and B-cell functions. That NR4As exert multilevel regulations of brain function and cardiac functions that protect immune survival from vascular cardiac diseases, and are the primary modulator to pro-inflammation and stimulator for variety of active genes and subunits started by estrogen and GCs-beta productions which followed by activating B-arrestins which activate B Adrenergic synthesis which has the roles of activating Nrf2 productions for adopting antioxidative functions, heme oxygenase, vasoconstriction functions, and anti-inflammatory growth mediated by Ang2-AT2 and VEGF-A synthesis.

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Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Cited by 28 publications

References 243 publications

Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B‐cell lymphomas

Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B‐cell lymphomas

Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy

GCs-beta and B-arrestins Regulate Nrf2 via NR4As Productive Pathway Mediated by B-adrenergic for Anti-inflammation and Adopting Myocardial and Immune Functions

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